The purpose of this application is to examine the regulation of virus infections by natural killer (NK) cells and other natural effector systems and to study how the NK cells interact with specific immune mechanisms and interferon (IFN) to bring about clearance of virus infection. A variety of viral infections will be used in the mouse model, including infections with lymphocytic choriomeningitis, murine cytomegalo, herpes simplex, vaccinia, Pichinde, and mouse hepatitis (MHV) viruses. These and several other viruses and variants will be screened for sensitivity to NK cells in vivo, and this will be correlated with their sensitivity to NK cell mediated lysis in vitro, with the aim of determining what property of a virus confers sensitivity to NK cells. The regulation of virus infections by lymphokine activated killer (LAK) cells will be examined, with the aim of developing therapeutic protocols to control virus infections with these cells. The regulation of mouse hepatitis virus infection by a recently discovered cytotoxic effect of B cells will be examined. This work should help define the parameters of natural immunity to virus infections and will determine whether natural effector cells can be used to control infections therapeutically.